Cocaine dependence is a widespread problem in the US with a significant personal and fiscal cost to society and the nation. More disturbingly a recent study showed that the cumulative incidence of cocaine use in the United States was 16% of the population or slightly more than 48,000,000 people. To date there are no drug treatments for cocaine dependence that have FDA indications for the treatment of cocaine dependent subjects. Given the psychosocial impact of the condition as described above, the need for the development of novel molecular targets for the treatment of cocaine dependence has never been as acute as it is today. We will study a novel molecular target, the serotonin 1B (5-HT1B) receptor as a possible treatment for cocaine dependence. There are a number of preclinical studies that implicate the 5-HT1B receptor in the pathophysiology of cocaine dependence. Pharmacological modulation of the receptor results in differential cocaine use and 5-HT1B knockout mice have increased vulnerability to cocaine use. However, the results of these studies are not entirely consistent. In order to clarify this issue, we propose to study the relationship between cocaine and 5-HT1B receptor in cocaine dependent subjects using state of the art molecular imaging and a validated self administration paradigm. We propose to use the novel 5-HT1B PET radioligand, [11C]-P943 to study 5-HT1B receptor binding in cocaine dependent subjects compared with healthy control subjects. We will also obtain measures of cocaine use, by studying subjects in a well validated, paradigm of cocaine self administration. In order to do this we will recruit a cohort of 8 subjects with a history of cocaine dependence and 8 matched healthy control subjects who have never used illicit substances. All subjects will have one PET scan with [11C]-P943 to quantify cortical and subcortical 5-HT1B receptor distribution. Subjects with a history of cocaine dependence will also undergo a self administration paradigm to obtain parameters related to vulnerability to use cocaine. We will also study whether 5-HT1B receptor binding and cocaine use in the self administration paradigm are correlated with each other. The successful completion of this project will allow further study of molecules that target the 5-HT1B receptor and modulate cocaine use. PUBLIC HEALTH RELEVANCE: Cocaine dependence is a widespread problem in the US, with a significant personal and fiscal cost to society and the nation. As there are no well validated drug treatments for individuals with cocaine dependence, this project will study the role of a specific system as a possible treatment target for the management of individuals with cocaine dependence. Successful completion of this project will allow for the development of novel treatments to help patients and their families combat this problem.